Liposomal irinotecan and PARP inhibitors are therapies useful in the treatment of cancer. Liposome encapsulated irinotecan formulations of the topoisomerase inhibitor irinotecan provide sustained exposure of irinotecan and the metabolite SN-38 in a tumor. ONIVYDE (irinotecan liposome injection) is an example of liposomal irinotecan recently approved in the United States for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. Poly(ADP-ribose) polymerases are a family of enzymes involved in DNA repair believed to act via two mechanisms: catalytic inhibition and trapping of PARP-DNA complexes, and inhibition of this repair pathway can result in cell death following DNA damage. PARP inhibitors are a new class of chemotherapeutic agents currently in development for the treatment of various cancer types.
While certain combinations of PARP and topoisomerase inhibitors have shown to be synergistic in in vitro assays, the clinical development of PARP inhibitor and topoisomerase inhibitor combinations has been limited due to increased toxicities and resultant dose reductions, thereby limiting the potential clinical utility of the combination. For example, significant myelosuppression was seen in a dose-escalation study of veliparib and topotecan, wherein the maximum tolerated dose was exceeded at the first planned dose level. Most PARP inhibitors are being developed to date solely as monotherapies. As a result, there is a need for methods to safely and effectively combine a PARP inhibitor with a Top1 inhibitor to treat cancer.